Tumor associated monoclonal antibodies (mAbs) are therapeutic agents when used as selective carriers of cytotoxic agents to malignancies. This hypothesis is tested in animal model systems with mAbs directed toward antigens associated with human disease. The cytocidal agents employed are particle emitting radionuclides. The relative efficacy is evaluated in the appropriately validated murine tumor xenograft model system. The radionuclides chosen focus on appropriate alpha emitters and beta emitters. Current research continues to focus on Pb-212, a beta-emitting alpha particle source, in parallel with the alpha emitter, At-211. Ongoing pre-clinical trials employ chelating agents 1B4M-DTPA (aka MX-DTPA or tiuxetan) or CHX-A (double prime) DTPA. Both are well established in clinical applications; the former is a component of, Zevalin. The chemistry that makes Zevalin, the 1st FDA approved radiolabeled antibody therapeutic, possible was developed by the Chemistry Section. Nearly all ongoing studies now employ the 3rd generation bifunctional chelating agent, CHX-A (double prime) DTPA for sequestering In-111, Y-90, Bi-213, and Lu-177. Prior studies validated the use of CHX-A (double prime) DTPA in PET imaging with the cyclotron produced (refined and purified by the Chemistry Section) Y-86 through the number of PET imaging studies recently reported by the Chemistry Section regarding applications of Y-86 for PET imaging targeting HER2 and HER1(EGFR) for visualizing a variety of diseases such ovarian, colorectal, pancreatic, prostate cancer. Related studies on Y-86 for PET imaging targeting HER1(EGFR) for imaging mesothelioma have been published. Complementary to the development of Y-86 for immunoPET, the Chemistry Section continues to develop novel and superior bifunctional chelating agent useful for Zr-89 immunoPET. The current technology is cumbersome and not stable in vivo leading to bone deposition of released Zr-89. Lead compounds of significantly greater Zr-89 complex stability developed through this program of study have now been published and creation of bifunctional analogs has been achieved. Evaluation of these agents has started. Pre-clinical evaluation of novel bifunctional chelating agents and linkers for targeted radiotherapy continues to refine conjugation chemistry options and radiolabeling improvements. These refinements stem from provision of agents for peptide chemistry as well as for site-specific conjugation strategies amenable for use with both radio-lanthanides and alpha-particle emitting radionuclides. Novel linkage chemistry agents for site-specific linkage strategies such as click chemistry and carbohydrate modification strategies have been created. Pre-clinical At-211 studies have been initiated with dose escalation survival studies targeting HER2 linking At-211 to trastuzumab employing the linker reagent, N-Me-SAPS. Replication of these studies with inclusion of toxicity assessments will provide an optimal dose for extension forward into long-term therapy studies. At-211 has been produced and supplied to collaborators at Johns Hopkins in an effort to establish an At-211 users/ investigators consortium to accelerate evaluation of the therapy potentials of this radionuclide and its clinical translation. The highly extensive and focused pre-clinical investigation into the use of Pb-212 continues for the treatment of disseminated intraperitoneal disease, e.g., from either ovarian or pancreatic cancer. Development of Pb-212 continued through to an open Phase I clinical trial with 14 patients treated, patient accrual continuing, and additional sites being opened. Murine toxicology experiments by the Section in support of the IND along with development of numerous additional documents, studies, and SOPs by the Section insured this Phase 1 trial, the first in the world using Pb-212, would proceed forward. Thus, the Section has routinely been at the forefront of truly novel translational bench to bedside research. Evaluation of Pb-212 with specific mAbs and their combinations with chemotherapeutics continues systematically. A single dose of a single, targeted radionuclide lacks a rational basis for cancer therapy; the hypothesis is that combined modality therapies will achieve significant therapeutic enhancements. Substantial increases in median survival in model systems with single doses of Pb-212 conjugated to clinically relevant antibodies, e.g., trastuzumab or panitumumab have been achieved in combination with gemcitabine, paclitaxel, or carboplatin have been demonstrated. Actual mechanistic studies related to understanding in vivo cellular processes involved in tumor eradication are non-existent. The first 3 such studies have been reported by the Section to define the biological mechanisms at the cellular level of both damage response and repair as well as genetic regulation of the cell biology in response to high-LET radiation. Baseline studies revealed that not only are double strand break prevalent, but that the DNA repair mechanisms are compromised, that apoptosis is enhanced, and that cell cycle impacted. Inclusion of gemcitabine demonstrated how that drug promoted therapy, while ongoing studies integrating taxol into the therapy regimen assess the impact of that drugs mechanism on this therapy. Parallel genetic profiling studies have been completed with the first published, the 2nd submitted for publication, and the 3rd in preparation. Studies pertaining to trifunctional imaging agents combining radionuclidic imaging (SPECT or PET) and NIR dye (Optical imaging) incorporating PEG continue. Critical discoveries regarding self-aggregation, convalent vs. non-covalent bonding, and appropriate characterization puts a significant body of literature in doubt. This advance provides real understanding of basic chemistry for creation of directly quantitative dual modality molecular imaging agents. Collaborative studies continue to be executed; reagents and/or expertise are supplied to facilitate all researchers to expeditiously perform experiments to fully define the clinical impact of targeted radiation therapy. To this end, the Section continues to enjoy very strong and potent collaborations with the Metabolism Branch, NCI and with the Ludwig Institute, and has fully extended this activity to a collaborative relationship with AREVA Med and UAB to translate Pb-212 into its first clinical trial for treatment of disseminated ovarian cancer while extending At-211 collaborations to researchers at Johns Hopkins.